The present invention relates to a combinatorial high throughput screening (CHTS) experiment design method and system.
Combinatorial organic synthesis (COS) is an HTS methodology that was developed for pharmaceuticals. COS uses systematic and repetitive synthesis to produce diverse molecular entities formed from sets of chemical xe2x80x9cbuilding blocks.xe2x80x9d As with traditional research, COS relies on experimental synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to produce large libraries of compounds through successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. A library is a physical, trackable collection of samples resulting from a definable set of processes or reaction steps. The libraries comprise compounds that can be screened for various activities.
For a number of reasons, it is difficult to apply the methodology of COS to catalyzed chemical reactions. First, chemical reactions particularly industrial catalyzed chemical reactions can involve large numbers of factors and require investigation of enormous numbers of factor levels (settings). For example, even a simple commercial process may involve five or six critical factors, each of which can be set at 2 to 20 levels. A complex homogeneous catalyst system may involve two, three, or even more metal cocatalysts that can synergistically combine to improve the overall rate of the process. These cocatalysts can be chosen from a large list of candidates. Additional factors can include reactants and processing conditions. The number of tertiary, 4-way, 5-way, and 6-way factor combinations can rapidly become extremely large, depending on the number of levels for each factor.
Another problem is that catalyzed chemical reactions are unpredictable. T. E. Mallouk et al. in Science, 1735 (1998) shows that effective ternary combinations can exist in systems in which no binary combinations are effective. Accordingly, it may be necessary to search enormous numbers of combinations to find a handful of leads,xe2x80x9d i.e., combinations that may lead to commercially valuable applications.
One answer to this problem is to carefully select and organize the experimental space of the system. However in this respect, the challenge is to define a reasonably sized experimental space that will provide meaningful results. There is a need for an experimental protocol to specify arrangements of formulations and processing conditions for combinatorial high through put screening (CHTS) so that positive interactions of formulation and processing variables can be reliably and efficiently detected.
The present invention relates to an experimental design strategy for evaluating systems with complex physical, chemical and structural requirements by CHTS. The definition of the experimental space permits a CHTS reliable and efficient investigation of highly complex systems. In the method, an experimental space comprising levels of factors is designed according to an incomplete block design and an experimental space comprising levels of factors is designed by random selection. Separate CHTS experiments are effected on each experimental space to produce sets of results and best common results are selected from the sets.
In an embodiment, the invention relates to a CHTS method comprising (1) selecting factors for an experimental space, (2) selecting a degree of interaction (t) of the factors, (3) selecting a degree of replication (xcex), (4) selecting a block size (xcexa), (5) generating an experimental incomplete block design according to t, xcex and xcexa, (6) conducting a CHTS method according to the design, (7) randomly permuting levels of the factors in the design, (8) conducting a second CHTS method according to the permuted levels design and (9) identifying common levels from the experiments that represent best results.
The invention also relates to a system for conducting an experiment. The system comprises a reactor for effecting a CHTS method on an experimental space to produce results and a programmed controller for the reactor that defines an experimental space comprising levels of factors according to an incomplete block design and defines an experimental space comprising levels of factors by random selection.